3-sulfanilamido-6-substituted pyridazines and method of preparing the same



United States Patent @fiice 2,712,012 Patented June 28, 19553-SULFANH.AMIDO=6SUBSTITUTED PYRIDA- EAINES AND METHOD OF PREPARING THEline H. Clark, Damien, Conn., assignor to American Cyanla imid Company,New York, N. Y., a corporation of awe No Drawing. Application November10, 1954, Serial No. 468,144

10 Claims. (Ci. 260-2391) This invention relates tosulfanilamidopyridazines. More particularly, it relates to3-sulfanilamido-6-substituted pyridazines and methods of preparing thesame.

In United States Patent No. 2,371,115, issued March 6, 1945, a number ofpara-substituted benzene sulfonamidopyridazines are described which havechemotherapeutic activity and are valuable intermediates for theproduction of azo dyes of extraordinary light fastness. In copendingapplication, Serial Number 400,376, filed December 24, 1953, an improvedprocess for the production of sulfanilamidopyridazines using3,6-dichloropyridazine and sulfanilamide is described.

We have found that the sulfanilamido-6-chloropyridazine prepared by theimproved process of application, Serial Number 400,376 is useful as anintermediate in preparing the therapeutically useful 6-substitutedsulfanilamidopyridazines. These new compounds of the present inventionmay be illustrated by the following general formula:

BEN-Q3 o inn-Q a in which R is an alkyl, aralkyl or aryl radical. Thealkyl radicals may be, for example, methyl, ethyl, propyl, butyl, amyl,etc. The aralkyl radicals may be benzyl, phenethyl, phenpropyl,phenbutyl and the like. The aryl radicals may be phenyl, naphthyl, etc.

The compounds of the present invention are, in general, crystallinesolids having a melting point above 100 C. They can be recrystallizedfrom water or alcohols or a mixture of water and alcohol.

These compounds can be prepared by using3-sulfanilamido-6-chloropyridazine as an intermediate which is reactedwith, .for example, simple alcohols, phenol, benzyl alcohol, phenethylalcohol, and the like. It is usually desirable to heat the reactionmixture to a temperature within the range of 50 Cato 250 C. for a periodof from ten minutes to fifteen hours. An alkali metal such as sodium orpotassium is added to the alcohol to form the corresponding alcoholatewhich is then reacted with the 3-sulfanilamido-6-chloropyridazine.

The compounds of the present invention, when given orally, show greatersurvival in mice against pneumococcus Strain SVI than related compounds.The following Table I shows the detailed results obtained when usingsulfadiazine, sulfapyridazine and 3 sulfanilamido 6 methoxypyridazine.

(Median effective dose=290 (220380) mg./kg./day

SULFAPYRIDAZINE (Median effective dcse=880 (310-2500) mg./lrg./day

3-SULFANILAMID O6-METHOXYPYRIDAZINE 3. 0 8/40 20. 0 0.025 19 l. S l/402. 5

(Median effective dose=180 (140-220) mg./kg./day

Drug intake values are averages based on four tests of each drug diet.

Figures in parentheses indicate confidence limits for each median.

When the present compounds are fed to mice infected with severaldiiferent bacteria along with related compounds they show a greateractivity. This is illustrated in Table II below.

TABLE 2 Relative antibacterial activities RELATIVE ACTIVITY BASED ONORAL DOSAGE 1* Relative activity based on dosage=ED o oisulfadiazine/EDED of other drug.

The preparation of the therapeutically useful compounds of the presentinvention is described in greater detail in the following examples. Allparts are by weight unless otherwise indicated.

EXAMPLE 1 3-sulfanilamid0-6-meth0xypyridazine 2.3 parts of clean sodiummetal is dissolved in 50 parts of anhydrous methyl alcohol. 11.4 partsof 3-sulfanilamido-6-chloropyridazine is added and the mixture heated ina sealed tube 13 hours at -140 C. After the tube EXAMPLE 23-sulfanilamido-6-eth0xypyridazine 0.6 part of clean sodium metal isdissolved in 75 parts of absolute ethyl alcohol. 2.9 parts of3-sulfanilamido-6- chloropyridazine is added and the mixture heated in asealed tube 13 hours at -155 C. After the tube has cooled it is openedand the reaction mixture filtered, acidified with dilute acetic acid,then evaporated to dryness on the steam bath. The residue is dissolvedin 20 parts of 10% sodium hydroxide, chilled and acidified with diluteacetic acid. The crude product is filtered and then recrystallized fromwater-ethanol to give 3-sulfanilamido 6-ethoxypyridazine, melting point183-184 C.

3 EXAMPLE 3 0.6 part of clean sodium metal is dissolved in 75 parts ofn-propyl alcohol. 2.9 parts of 3-sulfanilamido-6-chloropyridazine isadded and the mixture heated in a sealed tube 13 hours at 145 l55 C.After the tube has cooled it is opened and the reaction mixturefiltered, acidified with dilute acetic acid, then evaporated to drynesson the steam bath. The residue is dissolved in 10 parts of sodiumhydroxide, chilled and acidified with dilute acetic acid. The crudeproduct is filtered and recrystallized from water-ethanol to give3-sulfanilamido-6-n-propoxypyridazine, melting point 184185 C.

EXAMPLE 4 3-sulfanilamido-6-i-pr0poxypyridazirze 0.6 part of cleansodium metal is dissolved in 75 parts of i-propyl alcohol. 2.9 parts of3-sulfanilamido-6-chloropyridazine is added and the mixture heated in asealed tube 13 hours at 145155 C. After the tube has cooled it is openedand the reaction mixture filtered, acidified with dilute acetic acid,then evaporated to dryness on the steam bath. The residue is dissolvedin ml. of 5% sodium hydroxide, chilled and acidified with dilute aceticacid. The crude product is filtered and recrystallized fromwater-ethanol to give 3-sulfanilamido-6-i-propoxypyridazine, meltingpoint 187188 C.

EXAMPLE 5 3-sulfanilamido-6n-hex0xypyridazine 0.6 part of clean sodiummetal is dissolved in 200 parts of n-hexyl alcohol. 2.9 parts of3-sulfanilamido-6-chloropyridazine is added and the mixture refluxedhours at 157 C. The excess alcohol is then vacuum distilled. The residueis suspended in ether, filtered, washed two times with ether, thendissolved in 20 parts of water and acidified with dilute acetic acid.The crude product is filtered out, then recrystallized fromwater-ethanol to give 3 sulfanilamido 6 n hexoxypyridazine, meltingpoint 140-141 C.

EXAMPLE 6 3-sulfanilamido-6-ph enoxypyridazine 0.6 part of clean sodiummetal is dissolved in parts of methyl alcohol. 2.9 parts of3-sulfanilamido-6-chloropyridazine and parts of phenol is added and thissolution heated to C. to drive off all traces of methyl alcohol andwater. The residue is heated at 140 C. for 9 hours, then the excessphenol is distilled off. The residue is suspended in ether, filtered,washed two times with ether, then dissolved in 20 parts of water andacidified with dilute acid. The crude product is filtered out, thenrecrystallized from Water-ethanol to give 3-sulfanilamido-6-phenoxypyridazine. The compound melts at 139-l40 C., resolidifies andmelts again at 160l6l C.

EXAMPLE 7 3-sulfanilamid0-6-benzyl0xypyridazine 0.6 part of clean sodiummetal is dissolved in parts of benzyl alcohol. 2.9 parts of3-sulfanilamido-6-chloropyridazine is added and the mixture heated 13hours at l45l47 C. The excess alcohol is then vacuum distilled. Theresidue is suspended in ether, filtered, washed two times with ether,then dissolved in 20 parts of water and acidified with dilute aceticacid. The crude product is filtered, then recrystallized from ethylalcohol to give 3 sulfanilamido 6 benzyloxypyridazine, melting point 200-20l C.

EXAMPLE 8 3-sulfanilamido-6-phenethoxypyridazine in which R is a memberof the group consisting of lower alkyl, phenyl lower alkyl and phenylradicals.

2. 3-sulfanilamido-6-lower alkoxypyridazines.

3. The compound 3-sulfanilamido-6-methoxypyridazine.

4. The compound 3-sulfanilamido-6-ethoxypyridazine.

5. The compound 3-sulfanilamido-6-i-propoxypyridazine.

6. The compound 3-sulfanilamido-6-phenoxypyridazine.

7. The compound 3-sulfanilamido-6-benzyloxypyridazine.

8. A method of preparing compounds having the general formula:

in which R is a member of the group consisting of lower alkyl, phenyllower alkyl and phenyl radicals which comprises heating3-sulfanilamido-6-chloropyridazine with the reaction product of analkali metal with an alcohol having the formula:

ROI-I in which R is as defined above.

9. A method of preparing a 3-sulfanilamido-6-lower alkoxypyridazinewhich comprises heating 3-su1fanilamido-6-chloropyridazine with thereaction product of an alkali metal with a lower alkyl alcohol.

10. A method of preparing 3-su1fanilamido-G-methoxy- F pyridazine whichcomprises heating 3-sulfanilamido-6- chloropyridazine With an alkalimetal methylate.

References Cited in the file of this patent UNITED STATES PATENTS2,371,115 Winnek et al. Mar. 6, 1945

1. COMPOUNDS OF THE GROUP HAVING THE FORMULA: